Neuropeptide Y ("NPY") is a 36 amino acid peptide related to and a member of the "PP" peptide family which includes peptide YY ("PYY") and pancreatic peptide ("PP") (See, Tatemoto, et al. Nature, 296, 659 (1982); Tatemoto, Proc. Natl. Acad. Sci USA, 79, 5485 (1982)). NPY is named for the presence of an N-terminal tyrosine and a C-terminal tyrosine amide and is the most abundant peptide neurotransmitter in the brain and central nervous system. NPY is found also in various parts of the peripheral nervous system. This peptide mediates several important biological activities through various receptors and receptor subtypes as discussed below.
In the brain, high NPY levels are found in the cerebral cortex, hippocampus, thalamus, hypothalamus and brainstem. Dense NPY staining occurs in the hypothalamic, brainstem and some limbic regions suggesting that NPY plays a role in somatic, sensory or cognitive brain function. Studies have suggested, also that NPY plays a role in the regulation of food intake, particularly in eating disorders including, for example, obesity, anorexia and bulemia, and memory retention and other cognitive functions, as well as anxiolysis and depression.
Additionally, NPY is found in both peripheral nerves and in the circulation. NPY appears to be a co-transmitter with norepinephrine, playing a role in vasoconstriction and hypertension, cardiac contractility, analgesia and hyperalgesia, as well as control of secretory activity in the intestine.
As noted, NPY and NPY analogs, mediate the noted biological functions through a family of closely related receptor and receptor subtypes. Presently, five receptor subtypes have been identified and are designated Y1 through Y5. Each receptor subtype generally is associated with different biological activities.
For example, the Y1 receptor is believed to be responsible for mediating many of the central and peripheral activities of NPY, including the anxiolytic and sedative effects, as well as the observed vasoconstrictive activities.
The Y2 receptor is predominant in the brain, particularly in the hippocampus. The Y2 receptor mediated effects are associated with inhibition of adenylate cyclase and inhibition of transmitter release. The Y2 receptor effects include vasoconstriction in some blood vessels, antisecretory effects in the intestine, enhanced memory retention, and inhibition of lipolysis.
The Y3 receptor effects are associated with inhibition of adenylate cyclase and elevation of intracellular calcium ion concentrations. Biological effects observed for Y3 include hypotension and bradycardia, inhibition of cardiac contractile force, inhibition of glutamate responsiveness and baroreceptor reflex, inhibition of catecholamine release and release of aldosterone.
The Y4 receptor(also referred to as "PP1" receptor) may be involved in pancreatic exocrine secretion and hormonal control and may be important in diabetes or conditions associated with diabetes.
The most recently identified receptor is Y5 (sometimes referred to as "Y1-like" or "Feeding" receptor) (See, Gerald et al., Nature, 382, 168 (1996) and Hu et al., J. Biol. Chem., 271, 26315 (1996)). This receptor is associated with food intake and may mediate eating disorders such as obesity, bulemia and anorexia. Recently, Y5 has been implicated in the mediation of epileptic states and thus, NPY may be an endogenous anticonvulsant agent (See, e.g. Woldbye et al. Nat. Med., 3, 761 (1997)).
For several articles describing NPY, NPY analogs and receptors, see, for example, Hipskind, P. and Gehler, D., "Annual Reports in Medicinal Chemistry," 31, pp. 1-10, Robertson ed., (1996); Grunemar, L. and Hakanson, R., "TiPS Reviews," Vol. 15, p. 153, Elsevier Science Ltd. (1994); Munglani, R. et al., "Drugs," 52(3), 371 (1996); and Balasubramaniam, A., "Peptides", 18(3), 445 (1997), and references cited therein.
Because of the biological importance of NPY and the receptors with which it interacts, researchers have sought mediators, particularly antagonists, as novel therapeutic agents. A variety of peptide derivatives and analogs have been prepared in which amino acid modifications, substitutions, and deletions have been made relative to NPY. See, e.g., Hipskind, supra.
Although it would be preferable to have an easily synthesized, physically and metabolically stable and perhaps orally active NPY modulating compound, only a few non-peptide antagonists have been prepared. For example, a few non-peptidyl antagonists include the following: ##STR1##
See Doughty, M. B. et al., Eur. J. Pharmacol., 185, 113 (1990); J. Pharmacol. Exp. Ther., 265, 172 (1993); ##STR2##
See, Chaurasia, C., J. Med. Chem., 37, 2242 (1994); ##STR3##
See, Rudolf, K., et al., Eur. J. Pharmacol., 271, R11-R13 (1994); Sautel, M., et al., Mol. Pharmacol., 50, 285 (1996); ##STR4##
See, Serradeil-Le Gal, C., et al., FEBS Lett., 362, 192 (1995); Serradeil-Le Gal, C., et al., Soc. Neurosci. Abstr. 376.14 (1994); ##STR5##
See, Wright, J. L., et al., Bioorg. Med. Chem. Lett., 6, 1809 (1996); Wright, J. L., et al., 211.sup.th ACS National Meeting, New Orleans, La. (1996); ##STR6##
See, for example, Bruns, R. et al., PCT publications, WO 96/12489 and 96/12490; U.S. Pat. No. 5,504,094 (Apr. 2, 1996); and, ##STR7##
See Peterson, J. M., et al., PCT Publication WO 96/14307.
Additionally, compounds of the following general structure, described in PCT publication, WO 97/34873 (published Sep. 25, 1997), are noted to be useful in the treatment of hyperphagia, obesity or diabetes: ##STR8##
Further, the following compound and related compounds are noted to be useful in NPY5 associated disorders and are disclosed in PCT publications, WO 97/20823, WO 97/20820, WO 97/20821. and WO 97/20822: ##STR9##
and WO 98/35944 and WO 98/35957 disclose substituted alkylamide NPY5 receptor antagonists.
See, also, L. Criscione, et al., Society for Neuroscience, 23, Abstract No. 231.2, (1997).
Other published compounds include the following general formulae: ##STR10##
(See, respectively, PCT publication, WO 96/35689, published Nov. 14, 1996--CRF1 receptor agonist or antagonist compounds useful for treating and diagnosis of stress related disorders; and PCT publication, WO 97/29110, published Aug. 14, 1997--CRF receptor antagonist compounds useful for treating disorders relating to hypersecretion of CRF); and, ##STR11##
(See, PCT Publication, WO 95/33748, published Dec. 14, 1995--endothelin receptor antagonists).
Obesity, defined as an excess of body fat relative to lean body mass, is associated with important psychological and medical morbidities, the latter including hypertension, elevated blood lipids, and Type II or non-insulin dependent diabetes mellitus ("NIDDM"). There are over 6 million individuals with NIDDM in the United States, including approximately 20% of the population 65 years or older. See, Harris et al., Int. J. Obes., 11, 275 (1987). Approximately 45% of males and 70% of females with NIDDM are obese, and their diabetes is substantially improved or eliminated by weight reduction. See, Harris, Diabetes Care, 14(3), 639 (1991).
The assimilation, storage and utilization of nutrient energy is a complex system central to survival of a warm-blooded animal. Among land-dwelling mammals, storage in adipose tissue of large quantities of metabolic fuel as triglycerides is crucial for surviving through periods of food deprivation. The need to maintain a fixed level of energy stores without continual alteration in the size and shape of an organism requires the achievement of a balance between energy intake and expenditure.
Models of obesity which use animals with mutations in the ob and db gene indicate that the animals have an altered metabolism of carbohydrates resembling Type II diabetes in humans. These animals show effects which resemble other aspects of obesity. In particular, mice with these mutations eat more food and expend less energy than lean control animals. The phenotype is similar to that observed in animals with lesions of the ventromedial hypothalamus which indicates that the noted mutations may interfere with the ability to properly integrate or respond to nutritional information within the central nervous system. See, for example, Coleman, Diabetologia, 9, 294 (1973)
These studies and others related to NPY and NPY receptors show that there is an interaction of a variety of mechanisms involved in the development and maintenance of obesity, overeating and apparently related disease states such as diabetes, or even other NPY mediated disease states such as anxiety and depression. These may include a variety of genetic factors including modifications in the ob, db and NPY genes or receptors, or gene products which affect or modulate these receptors or gene products, including control mechanisms of these receptors or gene products, or control mechanisms of other receptors or targets either upstream or downstream in the signaling pathway from the noted genes, receptors or other target molecules.
Given the variety of clinical states associated with eating disorders, including hyperphagia, obesity, diabetes, and other disease states related to the various mechanisms involved including, for example, NPY pathways, a need exists for additional compounds capable of modulating such activities. In particular, there is a need to provide new approaches for the treatment or prophylaxis of obesity, overeating and diabetes and other diseases which are mediated by the same or related pathways associated with these diseases.
WO 98/06703 (incorporated herein in its entirety) discloses that compounds of the general formula ##STR12##
wherein A, W, X, Y, Z, R.sub.1, R.sub.2 ', R.sub.6 and R.sub.7 are as defined therein, are monocyte chemoattractant protein 1 (MCP-1) receptor antagonists and are capable of inhibiting the binding of MCP-1 to its receptor. MCP-1, a chemokine (chemoattractant cytokine), appears to be involved in inflammation by acting on monocytes, activated memory T cells and on basophils. MCP-1 is a potent secretogogue of inflammatory mediators for monocytes and basophils and appears to have chemotactic activity for human monocytes and/or T cells. MCP-1 may also play a role in allergic hypersensitivity disease. Further, MCP-1 selectively activates the B1 integrin family of leukocyte adhesion molecule and may play a role in leukocyte interactions with the extracellular matrix. Thus, MCP-1 may not only trigger the initial arrest and adhesion of monocytes and T cells, but may also act to guide their migration in extravascular space.
WO 98/08847 (incorporated herein by reference in its entirety) discloses that compounds of the general formula ##STR13##
wherein R.sub.3, R.sub.5, A, B, D, E, G, J and K are as defined therein, are corticotropin releasing factor (CRF) antagonists, corticotropin releasing factor hormone (CRH) binding protein inhibitors and are also useful in the treatment of inflammatory disorders. The CRF antagonists were reported to be effective in the treatment of stress-related illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorders and cyclothymia; chronic fatigue syndrome; eating disorders such as anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder, post-traumatic stress disorder, pain perception such as fibromyalgia; headache; gastrointestinal diseases; hemorrhagic stress; ulcers; stress-induced psychotic episodes; fever; diarrhea; post-operative ileus, colonic hypersensitivity; irritable bowel syndrome; Crohn's disease; spastic colon; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; pain; asthma; psoriasis; allergies; osteoporosis; premature birth; hypertension, congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, multiinfarct dementia, Parkinson's disease, and Huntington's disease; head trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone; obesity; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; cancer; infertility; muscular spasms; urinary incontinence; hypoglycemia and immune dysfunctions including stress induced immune dysfunctions, immune suppression and human immunodeficiency virus infections; and stress-induced infections in humans and animals. CRH binding protein inhibitors were reported to be effective in the treatment of Alzheimer's disease and obesity.
WO 98/05661 (incorporated herein by reference in its entirety) discloses that compounds of the general formula ##STR14##
wherein R.sub.3, R5, A, B, D, E, G, K and Z are as defined therein, are CRF antagonists, CRH binding protein inhibitors and are also useful in the treatment of inflammatory disorders.
WO 98/08846 (incorporated herein by reference in its entirety) discloses that compounds of the general formula ##STR15##
wherein R.sub.3, R.sub.5, A, B, D, E, G and K are as defined therein, are CRF antagonists, CRH binding protein inhibitors and are also useful in the treatment of inflammatory disorders.
WO 98/07726 (incorporated herein by reference in its entirety) discloses that compounds of the general formula ##STR16##
wherein R, R.sub.1, R.sub.2, R.sub.3, n and q are as defined therein, are protein tyrosine kinase inhibitors and/or inhibitors of protein serine/threonine kinases. The compounds were reported to inhibit the tyrosine kinase activity of the receptor for the epidermal growth factor (EGF) and of c-erbB2 kinase. These receptor-specific enzyme activities play a key role in signal transmission in a large number of mammalian cells, including human cells, especially epithelial cells, cells of the immune system and cells of the central and peripheral nervous system. In various cell types, EGF-induced activation of receptor-associated protein tyrosine kinase (EGF-R-PTK) is a prerequisite for cell division and thus for the proliferation of the cell population. Inhibition of protein kinases, such as EGF-receptor-specific tyrosine kinase, inhibits the proliferation of the cells. The compounds were also reported to inhibit other protein tyrosine kinases that are involved in signal transmission mediated by trophic factors, for example abl kinase (such as v-abl kinase), kinases from the family of the src kinases (such as c-src kinase), lck, fyn, other kinases of the EGF family (such as c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase), members of the family of the PDGF receptor protein tyrosine kinases (such as PDGF receptor kinase, CSF-1 receptor kinase, Kit receptor kinase, VEGF receptor kinase and FGF receptor kinase), the receptor kinase of the insulin-like growth factor (IGF-1 kinase), and serine/threonine kinases (such as protein kinase C or cdc kinases), all of which play a part in growth regulation and transformation in mammalian cells, including human cells.
WO 97/49706 (incorporated herein by reference in its entirety) discloses that compounds of the general formula ##STR17##
wherein R.sub.1, R.sub.2 and R.sub.3 are as defined therein, are protein tyrosine kinase inhibitors.